There is a wide variation in activity in naturally occuring calcitonins with an approximate 40-fold range in biopotency. All natural calcitonins share some structural features. Each is 32 amino acids long with a C-terminal prolinamide and an N-terminal disulfide linked ring from position 1 through 7. Salmon 1 calcitonin, for example, has the following formula (Niall, H. D.(1969)Proc. Natl. Acad. Sci. USA 64,771-778): ##STR1## Other calcitonins occuring in nature resemble salmon 1 calcitonin in varying degrees (Queener, S. F. and Bell, N. H. (1975)Metabolism 24,555-567; Lasmoles, F. et al.(1985)Febs Lett. 180,113-116). Eel calcitonin differs from salmon 1 calcitonin by having the amino acid Asp at position 26, Val at position 27 and Ala at position 29. Chicken calcitonin differs from salmon 1 calcitonin by having the amino acid Ala at position 2, Ser at position 3, Asp at position 26, Val at position 27 and Ala at position 29. Salmon 2 calcitonin differs from salmon 1 calcitonin by having Asp at position 15, Phe at position 22, Ala at position 29 and Val at position 31. Salmon 3 calcitonin differs from salmon 1 calcitonin by having Met at position 8, Asp at position 15, Phe at position 22, Ala at position 29 and Val at position 31. The calcitonins of mammalian origin differ more markedly from salmon 1 calcitonin, as shown in the references above. The structural features responsible for the increased potency ( about 40 times) of ultimobranchial calcitonins relative to calcitonins of mammalian origin have not yet been fully determined.
Modifications of the N-terminal cysteine by acylation or by substitution with 3-mercaptopropionic acid (desaminocysteine) show slight increases in the hypocalcemic activity of human calcitonin (Rittel, W. et al. (1976) Experientia 32,246-248; U.S. Pat. No. 3,934,008). The replacement of both cysteines with L-.alpha.-aminosuberic acid (Asu) at position 7 in the calcitonin sequence generated an analog with an ethylene bond instead of the naturally occuring disulfide bond between residue 1 and 7. The Asu analog also lack the .alpha.-amino group and is thus isosteric to the 3-mercapto analog above. The [Asu.sup.1,7 ] eel calcitonin analog has comparable activity to the naturally occuring hormone with the disulfide bond. The [Asu.sup.1,7 ] analog offers many advantages in large scale peptide synthesis due to the stability of a carbon-carbon bond compared with the reactive sulfur-sulfur bond (Morikawa, T. et al. (1976)Experientia 32, 1104-1106; Yamauchi, H. et al. (1977) Endocrinol. Japan 24,281-285; Yamamoto, I. et al. (1981) Endocrinol. 108,698-702; Ohno, H. et al. (1981 ) Japan J. Pharmacol. 31,537-542; U.S. Pat. No. 4,086,221).